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GRB2 promotes thymocyte positive selection by facilitating THEMIS-mediated inactivation of SHP1
The T-lineage restricted protein THEMIS has been shown to play a critical role in T cell development. THEMIS, via its distinctive CABIT domains, inhibits the catalytic activity of the tyrosine phosphatase SHP1 (PTPN6). SHP1 and THEMIS bind to the ubiquitous cytosolic adapter GRB2, and the purported...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10114920/ https://www.ncbi.nlm.nih.gov/pubmed/37067793 http://dx.doi.org/10.1084/jem.20221649 |
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author | Choi, Seeyoung Hatzihristidis, Teri Gaud, Guillaume Dutta, Avik Lee, Jan Arya, Awadhesh Clubb, Lauren M. Stamos, Daniel B. Markovics, Adrienn Mikecz, Katalin Love, Paul |
author_facet | Choi, Seeyoung Hatzihristidis, Teri Gaud, Guillaume Dutta, Avik Lee, Jan Arya, Awadhesh Clubb, Lauren M. Stamos, Daniel B. Markovics, Adrienn Mikecz, Katalin Love, Paul |
author_sort | Choi, Seeyoung |
collection | PubMed |
description | The T-lineage restricted protein THEMIS has been shown to play a critical role in T cell development. THEMIS, via its distinctive CABIT domains, inhibits the catalytic activity of the tyrosine phosphatase SHP1 (PTPN6). SHP1 and THEMIS bind to the ubiquitous cytosolic adapter GRB2, and the purported formation of a tri-molecular THEMIS–GRB2–SHP1 complex facilitates inactivation of SHP1 by THEMIS. The importance of this function of GRB2 among its numerous documented activities is unclear as GRB2 binds to multiple proteins and participates in several signaling responses in thymocytes. Here, we show that similar to Themis(−/−) thymocytes, the primary molecular defect in GRB2-deficient thymocytes is increased catalytically active SHP1 and the developmental block in GRB2-deficient thymocytes is alleviated by deletion or inhibition of SHP1 and is exacerbated by SHP1 overexpression. Thus, the principal role of GRB2 during T cell development is to promote THEMIS-mediated inactivation of SHP1 thereby enhancing the sensitivity of TCR signaling in CD4(+)CD8(+) thymocytes to low affinity positively selecting self-ligands. |
format | Online Article Text |
id | pubmed-10114920 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-101149202023-10-17 GRB2 promotes thymocyte positive selection by facilitating THEMIS-mediated inactivation of SHP1 Choi, Seeyoung Hatzihristidis, Teri Gaud, Guillaume Dutta, Avik Lee, Jan Arya, Awadhesh Clubb, Lauren M. Stamos, Daniel B. Markovics, Adrienn Mikecz, Katalin Love, Paul J Exp Med Brief Definitive Report The T-lineage restricted protein THEMIS has been shown to play a critical role in T cell development. THEMIS, via its distinctive CABIT domains, inhibits the catalytic activity of the tyrosine phosphatase SHP1 (PTPN6). SHP1 and THEMIS bind to the ubiquitous cytosolic adapter GRB2, and the purported formation of a tri-molecular THEMIS–GRB2–SHP1 complex facilitates inactivation of SHP1 by THEMIS. The importance of this function of GRB2 among its numerous documented activities is unclear as GRB2 binds to multiple proteins and participates in several signaling responses in thymocytes. Here, we show that similar to Themis(−/−) thymocytes, the primary molecular defect in GRB2-deficient thymocytes is increased catalytically active SHP1 and the developmental block in GRB2-deficient thymocytes is alleviated by deletion or inhibition of SHP1 and is exacerbated by SHP1 overexpression. Thus, the principal role of GRB2 during T cell development is to promote THEMIS-mediated inactivation of SHP1 thereby enhancing the sensitivity of TCR signaling in CD4(+)CD8(+) thymocytes to low affinity positively selecting self-ligands. Rockefeller University Press 2023-04-17 /pmc/articles/PMC10114920/ /pubmed/37067793 http://dx.doi.org/10.1084/jem.20221649 Text en This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply. https://creativecommons.org/licenses/by-nc-sa/4.0/http://www.rupress.org/terms/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Brief Definitive Report Choi, Seeyoung Hatzihristidis, Teri Gaud, Guillaume Dutta, Avik Lee, Jan Arya, Awadhesh Clubb, Lauren M. Stamos, Daniel B. Markovics, Adrienn Mikecz, Katalin Love, Paul GRB2 promotes thymocyte positive selection by facilitating THEMIS-mediated inactivation of SHP1 |
title | GRB2 promotes thymocyte positive selection by facilitating THEMIS-mediated inactivation of SHP1 |
title_full | GRB2 promotes thymocyte positive selection by facilitating THEMIS-mediated inactivation of SHP1 |
title_fullStr | GRB2 promotes thymocyte positive selection by facilitating THEMIS-mediated inactivation of SHP1 |
title_full_unstemmed | GRB2 promotes thymocyte positive selection by facilitating THEMIS-mediated inactivation of SHP1 |
title_short | GRB2 promotes thymocyte positive selection by facilitating THEMIS-mediated inactivation of SHP1 |
title_sort | grb2 promotes thymocyte positive selection by facilitating themis-mediated inactivation of shp1 |
topic | Brief Definitive Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10114920/ https://www.ncbi.nlm.nih.gov/pubmed/37067793 http://dx.doi.org/10.1084/jem.20221649 |
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